The objective of this portion of the study is to examine a toxic effect of digitalis glycosides, decreased myocardial extensibility, which appears during the recovery from hypoxia in cardiac muscle. The relationships between drug dosage, inotropic effect, and this toxic manifestation of the drug in terms of overall cardiac performance will be evaluated using the isolated cat papillary muscle preparation and the isolated canine heart. The physiological importance of this toxic manifestation of digitalis glycosides will be determined and its relationships to other toxic manifestations of the drug. In addition this decrease in extensibility following recovery from hypoxia in the presence of digitalis glycosides provides a unique opportunity for studying the passive properties of cardiac muscle and the interrelationships between contractile performance, myocardial fiber length, interbeat interval, inotropic and neural-hormonal background, and the resting properties of cardiac muscle. This project is directed at defining the mechanism(s) whereby the atrial systole-ventricular systole (As-Vs) interval influences left ventricular (LV) function during cardiac pacing. Recently reported data suggests that mitral regurgitation (MR) may account for the observed depression of LV function during ventricular pacing and during atrioventricular pacing with an inappropriate As-Vs interval. In canine right heart bypass preparations, the effects of atrial, ventricular and sequential atrioventricular pacing at constant heart rate (HR), stroke volume and aortic pressure (AP) on left atrial, LV, and mitral valve dynamics will be studied before and after prosthetic mitral valve replacement. MR will be assessed with a dye indicator under each experimental condition. The proposed experiments should clarify the mechanisms whereby LV performance is closely related to the As-Vs interval during cardiac pacing. Elucidation of this mechanism(s) appears important to appropriate application of cardiac pacing in patients with heart disease, particularly under conditions of marginal or depressed myocardial function.